The present invention relates to the synthesis of montelukast, a pharmaceutical agent, as well as to intermediates and processes useful in the synthesis.
Montelukast, chemically [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, has the following structure of formula (1):

Montelukast monosodium salt (montelukast sodium) is commonly used for treatment of asthma and/or seasonal allergies. It is marketed under the brand name SINGULAIR® (Merck) in the form of oral tablets, chewable tablets, and granules.
U.S. Pat. No. 5,565,473 to Belley et al. (see also corresponding EP 0 480 717) discloses a genus of pharmaceutically useful compounds that encompasses montelukast and salts thereof. Example 161 in connection with example 146 of U.S. Pat. No. 5,565,473 disclose the synthesis of montelukast sodium as follows:

THP as used herein means tetrahydropyranyl group.
Many other synthetic schemes are proposed in U.S. Pat. No. 5,565,473 for making unsaturated hydroxyalkylquinoline acids, which may generically include montelukast. However, none of these other schemes were specifically applied to making montelukast. For example, Method B in U.S. Pat. No. 5,565,473 comprises reacting a compound of “general formula (XII)” with an organometallic compound of formula R2M to give a compound of “general formula (Ia)”. Applying the corresponding substituent groups for montelukast, the method would follow the scheme below, wherein the compound of formula (2) is the representative compound of “general formula (XII)”:
M is suggested to be MgBr or Li in Method A. The only disclosed process for making the compounds of “general formula (XII)” is not desirable for making montelukast, i.e. for making the hypothetical compound of formula (2). Specifically the process in Method B calls for a coupling reaction with a compound of “general formula (XI).” If applied to the corresponding substituents for montelukast, the reaction would be as follows:
But this process cannot provide the compound (2) stereoselectively in the R-configuration as suggested above, which is required for the montelukast synthesis. Instead, only a racemic product may be obtained and no method has been suggested how to resolve the racemate into single enantiomers.
A suitable process for making montelukast starts from a methyl ester compound (18).
The compound (18) is a known compound of the prior art (see Compound XXVII in EP 480717) and can be produced by Steps 1-2 of the example 146 in EP 480717. It can be isolated in solid form as a monohydrate.
In an earlier patent application by some of the present inventors, Published Application No. US-2005-0245568-A1 filed Mar. 17, 2005, an acetylthio ester compound of formula (20)
was disclosed as an intermediate in a process for making montelukast and may be produced from the compound (18) as shown in the following reaction scheme:
The compound (20) may be reacted, optionally after its conversion to the thiol compound (3)
by treatment with hydrazine as described more fully in the above-mentioned US-2005-0245568, with a compound of formula (5):
wherein in the above formulas R is hydrogen or C1-C4 alkyl group, and L is a leaving group selected from a halogen or an alkyl- or aryl-sulfonyloxy group, to form a compound of formula (2) as in U.S. Pat. No. 5,565,473, or more generally (2a):
wherein R is H or a C1-C4 alkyl group. Thus, when R is hydrogen in formula (5), the compound (2) is directly formed. When R is a C1-C4 alkyl group in formula (5), then the compound of formula (2a) is formed. L is described as typically representing a chloro, bromo, mesyloxy, besyloxy or tosyloxy group. The reaction can take place in an inert solvent in the presence of a base and preferably under the atmosphere of an inert gas. The compounds of formula (2) and (2a) can be converted to montelukast or a salt thereof, generally by methylmagnesium halide, as shown in U.S. Pat. No. 5,565,473, optionally with hydrolysis.
In an alternate reaction pathway, which has been disclosed in another application filed by some of the present inventors—Published Application US-2005-0245569-A1 filed Mar. 17, 2005—the compound (20) is subjected to a reaction with methyl lithium in an inert solvent such as tetrahydrofuran, to form compound (6) as shown in the following reaction scheme:

In a next step, the compound (4) is made in situ from the compound of formula (6) by a reaction with hydrazine and it may be subsequently converted to montelukast. The reaction scheme can be expressed as follows:

It would be desirable to provide an alternate way to make montelukast which would be suitable for a large scale production and/or to improve the above described various methods. In particular, processes that can achieve good yields and high purity and that can be reliably controlled are important in industrial pharmaceutical chemistry.